The present invention relates to methods and apparatus for modulating neural plasticity in the nervous system. Neural plasticity includes phenomena such as memory and learning consolidation processes, as well as recovery of function following traumatic brain injury. The methods of the present invention are directed to modulating neural plasticity, improving memory and learning consolidation processes, cognitive processing, and motor and perceptual skills in both normal subjects and subjects suffering from chronic memory impairment, alleviating symptoms and improving outcome in subjects suffering from traumatic brain injury, preventing the development of epilepsy in subjects prone to developing this condition, and treating persistent impairment of consciousness. These methods employ electrical stimulation of the vagus nerve in human or animal subjects via application of modulating electrical signals to the vagus nerve by use of a neurostimulating device.
Vagal Afferents and Their Influence on Physiology and Behavior
The vagus nerve comprises both somatic and visceral afferents (inward conducting nerve fibers that convey impulses toward a nerve center such as the brain or spinal cord) and efferents (outward conducting nerve fibers that convey impulses to an effector to stimulate the same and produce activity). The vast majority of vagal nerve fibers are C fibers, and a majority are visceral afferents having cell bodies lying in masses or ganglia in the neck. For the most part, the central projections terminate in the nucleus of the solitary tract, which sends fibers to various regions of the brain such as the hypothalamus, thalamus, and amygdala. Other projections continue to the medial reticular formation of the medulla, the cerebellum, the nucleus cuneatus, and other regions. The solitary nucleus has important pathways to brain regulatory networks, including the serotonergic nuclei and the noradrenergic nuclei. These neurotransmitter systems are crucial for memory, learning, cognitive and sensory/perceptual processing, and motor skills. These neurotransmitters also prevent the development of epilepsy, i.e., they are antiepileptogenic, and are important for the processes that subserve brain recovery following traumatic injury.
The majority of vagus nerve fibers are viscerosensory afferents originating from receptors located in the lungs, aorta, heart, and gastrointestinal tract, and convey, among other things, cardiopulmonary and nocicepive information to various forebrain and brainstem structures (Cechetto, D. F. (1987) Federation Proceedings 46:17-23). Three populations of vasal afferents are known to exist: the vastly abundant unmyelinated C fibers involved in pain mediation, and small myelinated B fibers and large A fibers which subserve autonomic reflexes and probably more complex visceroendocrine responses, such as glucose metabolism and fluid homeostasis (Barraco, I. R. A. (1994) Nucleus of the Solitary Tract, CRC Press, Boca Raton). Nearly all vagal afferents terminate in the nucleus of the solitary tract (NTS), where the information they carry is first integrated before being divergently projected to each rostral level of the neuroaxis. Because NTS neurons impinge on a number of CNS structures and regions, including the hypothalamus, hippocampus, amygdaloid complex, dorsal raphe nucleus, and mesencephalic reticular formation (Rutecki, P. (1990). Epilepsia 31 (Suppl. 2):51-56), an equally large number of cognitive, somatic, and visceral operations can be initiated or coordinated with autonomic information. Thus, as one might expect, neural signals sent via vagal afferents have a profound impact on CNS function that, in turn, influence general behaviors and arousal. For instance, electrical stimulation of the cervical vagus can modify the electrophysiological profile of neocortical, thalamic, and cerebellar neurons. These and other changes in supramedullary circuits are thought to precipitate overt changes in, for example, sleep, feeding behavior, responsiveness to noxious stimuli, and monosynaptic muscular reflexes (Rutecki, supra).
Vagus Nerve Stimulation and the Brain
Vagus nerve stimulation has been shown to cause activation of several parts of the brain that are specifically involved in cognitive processing, memory, learning, sensory and motor processing, and affects regions of the brain that are prone to developing epilepsy or which regulate the development of epilepsy (Naritoku et al. (1995) In Ashley et al., Eds., Traumatic Brain Injury Rehabilitation, CRC Press, Boca Raton, pp. 43-65). These studies demonstrate that vagus nerve stimulation activates the amygdala and cingulate cortex, which are involved in learning and cognitive processing. Such stimulation also activates several thalamic nuclei which serve relay functions. In addition, it activates several sensory nuclei, including the auditory, visual, and somatic sensory systems. Finally, vagus nerve stimulation activates monoaminergic nuclei, especially the locus ceruleus and A5 groups, which provide norepinephrine to the brain. Monoamines are crucial for both learning and memory, and for preventing the development of epilepsy (Jobe et al. (1981) Biochem. Pharmacol. 30:3137-3144).
Modulation of Memory by Arousal
Both anecdotal and scientific reports have long suggested that some memories are remembered far more distinctly than others when those memories were stored at the time of a significant emotional or stressful life event. This appears to be an important memory mechanism by which the brain selectively enhances the storage and retrievability of more important memories, while minimizing interference from those that are comparatively inconsequential. The research to date indicates that the storage of permanent memories is susceptible to enhancing or disrupting influences shortly after an initial exposure to salient information (McGaugh, J. L. (1989) Annual Review of Neuroscience 12:255-287; McGaugh, J. L. (1990) Psychological Science 1:15-25; Squire, L. R. (1987) Memory and Brain, Oxford University Press, New York). In clinical and animal studies, improved retention can be produced by a wide variety of treatments, including the peripheral administration of certain hormones, neuromodulators, and stimulant drugs, such as amphetamine. One factor which seems to be common to those agents that enhance memory is that most are related in some way to arousal.
Arousal is associated with the release of adrenal catecholamines and numerous other substances such as the pituitary hormones ACTH and vasopressin. Peripheral administration of these substances has consistently been shown to modulate memory in a dose- and time-dependent fashion (McGaugh et al. (1989) xe2x80x9cHormonal Modulation of Memoryxe2x80x9d In Brush et al., Eds., Psychoendocrinology, Academic Press, New York). For instance, when moderate doses of epinephrine or its agonists are given shortly after training on a memory task, there is enhancement of retention performance measured some time later (Gold et al. (1977) Behavioral Biology 20:197-207). Importantly, many substances that modulate memory when either endogenously released or delivered systemically do not freely cross the blood-brain barrier, and are therefore unlikely to influence memory by direct pharmacological action on the brain. Instead, they appear to activate peripheral receptors that in turn send neural messages to those central nervous system (CNS) structures involved in memory consolidation.
Role of the Vagus Nerve in Mediating Arousal-Induced Memory Modulation
The vagus nerve appears to be at least partially responsible for the observed memory-modulating effects of peripherally-acting agents. Williams et al. ((1991) xe2x80x9cVagal afferents: A possible mechanism for the modulation of memory by peripherally acting agentsxe2x80x9d In: Frederickson et al., Eds., Neuronal control of bodily function, basic and clinical aspects: Vol. 6., Peripheral signaling of the brain: Role in neuralimmune interactions, learning and memory, Hogrefe and Huber, Toronto, pp. 467-472) and Williams et al. ((1993) Physiology and Behavior 54:659-663) demonstrated that severing the vagus nerve below the level of the diaphragm attenuated the memory-enhancing effects of 4-OH amphetamine, an amphetamine derivative that does not freely enter the CNS, as well as the memory-impairing effects of peripherally-administered Leu-enkephalin. Similar attenuation has also been demonstrated with respect to the memory-modulating capacity of cholecystokinin (Flood et al. (1987) Science 234:832-834).
Clinical Measurements of Memory Modulation Induced by Arousal
Arousal has also been demonstrated to affect memory performance in humans. Nielson et al. ((1996) Neurobiology of Learning and Memory 66:133-142) studied the effects of muscle-tension-induced arousal on memory storage and later retention performance. In that study, a moderate level of muscle-tension-induced arousal was produced by having subjects, young college students, squeeze a hand dynamometer at various times during or following presentation of one practice and four 20-item word lists presented as slides (one every 5 sec.). Thus, each subject participated in four arousal conditions: no muscle tension; muscle tension (100 sec.) during learning of the list (encoding); muscle tension during the 100-sec. memory consolidation interval (storage); and muscle tension (100 sec.) during the immediate recall of the words (retrieval). List order remained the same for all subjects, but the order of arousal conditions was counterbalanced. A final recognition test was given 5 min. after completion of all lists. The results demonstrated that muscle-tension-induced arousal during the memory consolidation interval significantly enhanced final recognition performance.
In another phase of this investigation, subjects were given a series of two practice and twelve 200-word paragraphs to read. Half of the test paragraphs contained highlighted words. Immediately following completion of each paragraph, two questions (one factual and one logical-inferential) were asked about the content of that paragraph. In addition, for the paragraphs containing highlighted words, subjects were asked to recall as many of the highlighted words as they could. For the muscle-tension arousal paragraphs, immediately after the paragraph was completed, the subject was handed the hand dynamometer and asked to squeeze it during the answering of the questions and the recalling of highlighted words. Following completion of the final paragraph and all questions, a final recognition test of all highlighted words was given. The results indicated significant enhancement of retention performance for the muscle-tension arousal paragraphs compared to the no-tension paragraphs, indicating that arousal can enhance memory storage in a working-memory task.
This experiment was replicated using elderly subjects (Nielson et al. (1994) Behavioral and Neural Biology 62:190-200). In this experiment, there were 22 normotensive elderly subjects, 21 elderly subjects taking either calcium-channel blockers or angiotensin-converting enzyme inhibitors to control hypertension, and 21 elderly subjects taking beta-blocker antihypertensive medications. The normotensive elderly subjects and those taking non-beta-blocker medications all showed enhanced long-term memory performance as a result of muscle-tension-induced arousal. However, those subjects chronically taking beta-receptor-antagonist medications showed no enhancement of retention performance. These findings suggest that when arousal occurs, there is an enhanced release of adrenal catecholamines (epinephrine and norepinephrine), and that these substances activate peripheral receptors that send neural messages to the brain to modulate memory storage processes. When these receptors are antagonized by beta-blocker-type antihypertensive medications, the normal processes of memory modulation are impaired. Since epinephrine and norepinephrine do not freely cross the blood-brain barrier, their release by arousal likely modulates memory by causing the transmission of neural messages to the brain, possibly via the vagus nerve pathway. Therefore, antagonizing peripheral beta receptors by beta-blocker-type antihypertensive medications prevented the initiation of these messages by the receptors, thus effectively attenuating the normally occurring modulation of memory storage processes by arousal.
Possible Role of Specific Central Serotonergic and Noradrenergic Pathways in the Modulation of Memory by Vagus Nerve Stimulation
The dorsal raphe nucleus is one of two monoaminergic brainstem nuclei, the other being the locus coeruleus, that receives indirect input from vagal afferents. Both nuclei then project that information to various other brain structures implicated in learning and memory processes, such as the amygdaloid complex, hippocampus, and mesencephalic reticular formation (Vertes et al. ( 1994) Journal of Comparative Neurology 340:11-26). Thus, the dorsal raphe nucleus and locus coeruleus are well suited to regulate the memory-modulating effects of autonomic arousal. In addition, the dorsal raphe nucleus interacts with the amygdaloid complex to produce conditioned fear responses to inescapable shock and in learned-helplessness paradigms (Maier et al. (1993) Behavioral Neuroscience 107:377-788). Elevations in the release of serotonin by the dorsal raphe nucleus also reportedly increase anxiety (Iversen (1984) Neuropharmacology 23:1553-1560). It is therefore possible that changes in autonomic activity and arousal are reflected in alterations of dorsal raphe nucleus activity and the subsequent release of serotonin onto neurons found in the amygdaloid complex. It is therefore possible that changes in autonomic activity and arousal are transmitted to the brain via the vagus nerve and are reflected in alterations in the activity of neurons in the dorsal raphe nucleus and the subsequent release of serotonin onto neurons of the amygdaloid complex, a brain structure well-known to be involved in the modulation of learning and memory.
Noradrenergic systems are also known to modulate memory consolidation and amygdaloid complex activity (c f. McGaugh (1989) Annual Review of Neuroscience 12:255-287); however, Holdefer et al. ((1987) Brain Research 417:108-117) demonstrated that locus coeruleus-maintained discharge does not correlate with the memory modulation produced by peripherally-injected 4-OH amphetamine, D-amphetamine, or epinephrine. Although the locus coeruleus receives indirect vagal input, it also receives serotonergic projections from the dorsal raphe nucleus. Consequently, dorsal raphe nucleus activity might suppress the responsiveness of locus coeruleus neurons to autonomic stimulation, thereby increasing serotonergic control over the amygdaloid complex and other brain areas during the memory consolidation period. This hypothesis is supported directly by studies of Naritoku et al.((1995) In Ashley et al., Eds., Traumatic Brain Injury Rehabilitation, CRC Press, Boca Raton, pp. 43-65), which demonstrated activation of the locus ceruleus and A5 nuclei, which are noradrenergic neurons. Preliminary evidence of Krahl et al. ((1994) Society for Neuroscience Abstracts 20:1453) also indicates that cells found in the dorsal locus coeruleus respond differentially to those found in either the ventral locus coeruleus or subcoeruleus following vagus nerve stimulation.
Modulation of Memory by Peripherally-Acting Substances
Previous research has suggested that the vagus nerve plays a role in the modulation of learning and memory brought about by peripherally-acting substances such as catecholamines, peptides, etc. (Williams et al. (1991) In Frederickson et al., Eds., Neuronal Control of Bodily Function, Basic and Clinical Aspects: Volume 6, Peripheral Signaling of the Brain: Role in Neural-Immune Interactions, Learning and Memory, Hogrefe and Huber, Toronto, pp. 467-472; Williams et al. (1993) Physiology and Behavior 54:659-663; Flood et al. (1987) Science 234:832-834). This work suggests that the vagus nerve may represent a neural pathway through which such substances alter retention performance. However, the effects of direct electrical activation of the vagus nerve on learning and memory in humans have not been previously studied.
Chemical vs. Direct Electrical Stimulation of the Vagus Nerve
1. Chemical Stimulation
Hormonal or chemical (drug) agents function by interacting with specific receptor proteins on neurons. When activated by a neurotransmitter, hormone, or drug, these receptor proteins then either: 1) cause a chemical change in the cell, which indirectly causes ion channels embedded in the membrane to either open or close, thus causing a change in the electrical potential of the cell, or 2) directly cause the opening of ion channels, which causes a change in the electrical potential of the cell. This change in electrical potential then triggers electrical events that are conducted to the brain by the axons of sensory nerves such as those contained in the vagus.
Neural activity is constantly being controlled by the endogenous release of hormones, neurotransmitters, and neuromodulators. However, for therapeutic or experimental purposes, changes in neural activity can also be produced by the administration of chemical or hormonal agents (drugs). When administered exogenously, these agents interact with specific proteins either inside neurons or on the surface of the cell membrane to alter cell function. Chemical agents can stimulate the release of a neurotransmitter or family of neurotransmitters, block the release of neurotransmitters, block enzymatic breakdown of neurotransmitters, block reuptake of neurotransmitters, or produce any of a wide variety of other effects that alter nervous system functioning. A chemical agent can act directly to alter central nervous system functioning or it can act indirectly so that the effects of the drug are carried by neural messages to the brain. A number of chemical/hormonal agents such as epinephrine, amphetamine, ACTH, vasopressin, pentylene tetrazol, and hormone analogs all have been shown to modulate memory. Some act by directly stimulating brain structures. Others stimulate specific peripheral receptors.
2. Electrical Stimulation
In contrast, electrical stimulation of a nerve involves the direct depolarization of axons. When electrical current passes through an electrode placed in close proximity to a nerve, the axons are depolarized, and electrical signals travel along the nerve fibers. The intensity of stimulation will determine what portion of the axons are activated. A low-intensity stimulation will activate those axons that are most sensitive, i.e., those having the lowest threshold for the generation of action potentials. A more intense stimulus will activate a greater percentage of the axons.
Electrical stimulation of neural tissue involves the placement of electrodes inside or near nerve pathways or central nervous system structures. Functional nerve stimulation is a term often used to describe the application of electrical stimulation to nerve pathways in the peripheral nervous system. The term neural prostheses describes applications of nerve stimulation in which the electrical stimulation is used to replace or augment neural functions which have been damaged in some way. One of the earliest and most successful applications of electrical stimulation was the development of the cardiac pacemaker. More recent applications include the electrical stimulation of the auditory nerve to produce synthetic hearing in deaf patients, and the enhancement of breathing in patients with high-level spinal cord injury by stimulation of the phrenic nerve to produce contractions of diaphragm muscles. Recently, electrical stimulation of the vagus nerve is being used to attenuate epileptic seizures.
The basis of the effects of electrical stimulation of neural tissue comes from the observation that action potentials can be propagated by applying a rapidly changing electric field near excitable tissue such as nerve or muscle tissue. In this case, the electrical stimulation, when passed through an electrode placed in close proximity to a nerve, artificially depolarizes the cell membrane which contains ion channels capable of producing action potentials. Normally, such action potentials are initiated by the depolarization of a postsynaptic membrane. However, in the case of electrical stimulation, the action potentials are propagated from the point of stimulation along the axon to the intended target cells (orthodromic conduction). However, action potentials also travel from the point of nerve stimulation in the opposite direction as well (antidromic conduction).
Gold and his co-workers have demonstrated that administration of glucose to rats or humans following a learning experience enhances later retention performance (Gold, P. E. (1986) Behavioral and Neural Biology 45:342-349; Manning et al. (1993) Neurobiology of Aging 14:523-528). Gold has suggested that vagus nerve stimulation may activate descending efferent vagus pathways which directly and indirectly stimulate the liver to release glucose into the systemic circulation. This increased plasma glucose has been postulated to serve as a second messenger to modulate the storage of memories. However, the present investigators recently demonstrated in rats that blocking descending vagus nerve pathways by a topical application of the local anesthetic lidocaine to the nerve did not attenuate memory enhancement produced by vagus nerve stimulation (Clark, K. B., Smith, D. C., Hassert, D. L., Browning, R. B., Naritoku, D. K., and Jensen, R. A. (submitted for publication)). Posttraining electrical stimulation of vagal afferents with concomitant efferent inactivation enhances memory storage processes in the rat (Society for Neuroscience Abstracts, 22). These results clearly indicate that the ascending neural messages resulting from vagus nerve stimulation are the active agent mediating the observed enhancement in memory storage processes.
Few experiments in contemporary neuroscience research employ direct nerve tract stimulation to alter global aspects of behavior such as the storage of memories. Most researchers attempt to alter memory and/or behavior by either administering a drug that activates specific neural systems or by electrically stimulating specific groups of neurons in the central nervous system. Thus, the present inventors"" discovery of vagus nerve stimulated enhancement of particular neural processes as disclosed herein is novel. In this case, stimulation of the vagus nerve results in the activation of a variety of processes in the brain that result in changes in brain function. It is likely that only some of these processes are related to the modulation of memory storage and that this stimulation also modulates other changes or plastic processes in the brain as well. That direct vagus nerve stimulation influences plastic processes related to brain development or the recovery of function from brain injury is a very good possibility given the already demonstrated effect on one major form of neural plasticity, i.e., memory storage.
Modulation of Memory in Rats by Electrical Stimulation of the Vagus Nerve
Jensen and co-workers (Clark, K. B., Krahl, S. E., Smith, D. C., and Jensen, R. A. (1994) Society for Neuroscience Abstracts 20: 802; Clark, K. B., Krahl, S. E., Smith, D. C., and Jensen, R. A. Neurobiology of Learning and Memory 63:213-216) demonstrated that direct electrical stimulation of the vagus nerve at a particular intensity (0.4 mA) and frequency (20 Hz) administered shortly after a learning experience resulted in a pattern of effects on retention performance similar to that reported following the administration of some drugs that do not freely cross the blood-brain barrier (chemical stimulation of peripheral receptors). In this experiment, vagus nerve stimulation (0.4 mA) given during the memory consolidation interval modulated later retention performance such that stimulated rats showed better memory. Stimulation at either a lower (0.2 mA) or higher (0.8 mA) intensity had no effect on retention.
Whether one could reasonably predict that this effect observed in rats might extrapolate to human beings is doubtful in view of the substantial differences in neuroanatomy and complexity of memory processes between laboratory rodents and humans. The experiments performed in rats were based on a single-trial training task of great simplicity, i.e., an inhibitory avoidance task. In this task, the animals were placed in a runway, one end of which was brightly illuminated, while the other end was darkened. As rats are nocturnal, burrowing animals, they typically move quickly from the lighted end into the darkened end when the door separating the two ends of the runway is opened. A mild electrical footshock was delivered in the darkened end. Immediately thereafter, each animal was removed from the runway and returned to its home cage, where it received either no stimulation or vagal stimulation through chronically implanted cuff electrodes on the left cervical vagus nerve. Retention was tested 24 hours later. Latency to step through into the darkened end was taken as the measure of retention.
In the case of human memory, especially verbal memory, the neural systems involved are much more complex than those involved in the learning of a simple avoidance training task by the rat. Learning of concepts, vocabulary, and procedures by humans is qualitatively and quantitatively different from a rat""s learning to avoid the end of a runway where punishment, i.e., a footshock, has occurred. Many human brain structures, such as those that mediate language, for example, do not even exist in the laboratory rat. It is therefore possible that the foregoing phenomenon observed in rats is limited to infrahumans, and it is therefore not reasonably predictable that vagal nerve stimulation modulation of memory in the laboratory rat would generalize to human subjects. The applicability of vagal nerve-stimulated modulation of learning of tasks such as complex verbal tasks has for the first time been demonstrated by the present inventors as disclosed herein.
Uniqueness of Vagus Nerve Stimulation in Modulating Memory
Vagus nerve stimulation is completely unlike other experimental manipulations known to modulate memory. Drugs, hormones, and electrical brain stimulation are all known to alter memory storage processes. For example, administration of adrenal hormones (such as epinephrine) or pituitary hormones (such as ACTH) after a learning experience results in the enhancement of memory in a dose-dependent manner. Very low doses are without effect; intermediate doses tend to improve retention performance; very high doses tend to cause amnesia. These hormonal substances and pharmacological agents are thought to act on memory processes by activating specific receptors in the periphery which, in turn, send neural messages to the brain to either enhance or impair the storage of memories.
In contrast, vagus nerve stimulation directly activates one principal nerve pathway connecting the central nervous system with peripheral structures located in the viscera. In this case, the step of chemically activating receptors in the periphery is avoided. Rather, action potential messages in the nerve are directly triggered by the electrical stimulation. These messages pass along the vagus nerve and activate those brain structures in which the nerve fibers terminate. The result is release of neurotransmitters and activation of still other brain structures. Following this, there are alterations in brain function such as the well-established reduction in epileptic seizures and the recently demonstrated enhancement in CNS plasticity, specifically, facilitation of memory storage processes.
Brain Neural Plasticity
The term xe2x80x9cneural plasticityxe2x80x9d can be viewed as encompassing those structural alterations in the brain that lead to changes in neural function. Such changes in neural function then lead to changes in behavior or in the capacity for behavior. Learning and memory can be thought of as one common form of neural plasticity. The storage of memories following a learning experience is the result of structural and functional changes that occur in specific groups of neurons. Every time something is learned, there is a change in that organism""s nervous system which encodes that new information. Such a change does not necessarily result in an immediate change in behavior; rather, it results in an alteration in behavior potential.
During development of the nervous system both before and after birth, there are profound plastic changes taking place which shape the structure and function of the brain. Before birth, groups of nerve cells form, migrate to their assigned location in the brain, and then make connections with other cells. Following birth, neurons continue to sprout new projections, and these branches expand dramatically in complexity, sometimes extending great distances, and making connections with other cells of the nervous system. This process, another form of neural plasticity, continues at a decreasing rate from the time of birth until adolescence.
Neural plasticity is thought to be moderated by a wide variety of cellular and molecular events, including transcription and translation of DNA, which produces cellular proteins that cause long-term changes in neuronal function. One such signal is thought to be the protein fos, which is produced by neurons under conditions of high activity. This protein signals the transcription of other proteins, and is thought to mediate long-term neuronal changes. It may be induced by several neurotransmitters, including excitatory amino acids and monoamines. Naritoku et al. ((1995) Epilepsy Research 22:53-62) demonstrated that fos is induced by stimulation of the vagus nerve in widespread areas of the brain (see FIG. 3), thus demonstrating that vagus nerve stimulation activates many areas in the brain, and furthermore, appears to induce the production of a protein that causes further transcriptional events that may in turn mediate neural plasticity.
Memory and Learning and Their Modulation
It is clear that learning and memory are not unitary processes and that there are different types of memory that are mediated by different brain structures. On one level of analysis, it is possible to distinguish between two broad classes of memories, xe2x80x9cexplicitxe2x80x9d and xe2x80x9cimplicit.xe2x80x9d When explicit memory is to be assessed, measures such as recall and recognition are used. These measures depend on the conscious recollection of previously stored information. Recognition performance is generally considered to be among the most sensitive measures of explicit memory. Tests of implicit memory infer learning from the effects that experience or practice has on the subject""s performance. For example, prior exposure to words will enhance later performance in recognizing these words when they are flashed very rapidly on a screen or presented as word fragments.
Another distinction between types of memory is that between xe2x80x9cproceduralxe2x80x9d and xe2x80x9cdeclarativexe2x80x9d memories. These are typically defined as xe2x80x9cknowing howxe2x80x9d and xe2x80x9cknowing that.xe2x80x9d Procedural memories include perceptual, cognitive, and motor skills, while declarative memory includes such things as facts, events, and routes between places. Both forms of memory can be modulated by various agents, although declarative memories are more subject to disease-produced amnesia than are procedural memories.
We know from our own every-day experiences that some occurrences or events are remembered clearly while others are remembered poorly or perhaps not at all. This is true of procedural and declarative memories whether assessed implicitly or explicitly. It is well established in laboratory animals that retention can be either impaired or enhanced by experimental treatments such as electrical brain stimulation, the administration of stimulant drugs, or the administration of hormones (McGaugh et al. (1972) Memory Consolidation, San Francisco, Albion Publishing Company). What is commonly reported is that retention performance, measured some time after the learning experience, can be modulated by changing the parameters of training or by the administration of chemical stimulation shortly after the time of training. Although the underlying mechanisms that mediate memory modulation are not well understood, it appears that several common principles may mediate differences in the quality of remembering.
One major variable influencing retention performance appears to be level of arousal. Early in the development of the behavioral sciences, the Yerkes-Dodson principle was described (Yerkes et al. (1908) Journal of Comparative Neurology and Psychology 18:459-482). This principle is characterized by an inverted U-shaped relationship between the amount of motivation or arousal and the resultant level of behavioral performance. This relationship can be seen between the level of arousal and the effectiveness of memory storage processes. For example, either low or very high levels of arousal produce relatively poor learning and memory. However, an intermediate level of arousal results in relatively good memory for a learning experience (McGaugh, J. L. (1973) Annual Review of Pharmacology 13:229-241). A similar curve showing an inverted U-shaped function is seen in the data obtained using laboratory rats and vagus nerve stimulation delivered after training. It is important to note that memory is modulated by post-training treatment. In such an experiment, the learning occurs in a normal state and then after training, the treatment is administered. Thus, the primary effects of the treatment are on the storage of the memory and not on other aspects of the experience such as perception or level of motivation.
Traumatic Brain Injury
Another form of neural plasticity is recovery of function following brain injury. As in the case of memory formation or brain development, in this case too there is a change in the ways that neurons interact with one another. When neurons are lost due to disease or trauma, they are not replaced. Rather, the remaining neurons must adapt to whatever loss occurred by altering their function or functional relationship relative to other neurons. Following injury, neural tissue begins to produce trophic repair factors, such as nerve growth factor and neuron cell adhesion molecules, which retard further degeneration and promote synaptic maintenance and the development of new synaptic connections. However, as the lost cells are not replaced, existing cells must take over some of the functions of the missing cells, i.e., they must xe2x80x9clearnxe2x80x9d to do something new. In part, recovery of function from brain traumatic damage involves plastic changes that occur in brain structures other than those damaged. Indeed, in many cases, recovery from brain damage represents the taking over by healthy brain regions of the functions of the damaged area. Thus, such recovery can be viewed as the learning of new functions by uninjured brain areas to compensate for the loss of function by other regions. Studies of the effect of vagus nerve stimulation on fos production demonstrate that such stimulation induces transcriptional events that produce proteins which in turn stimulate further cellular transcriptional activity (Hughes et al. (1995) Pharmacol. Rev. 47:133-178). Increases in neuronal cellular activity will enhance the recovery of function after traumatic brain injury.
Traumatic brain injury results from a wide variety of causes including, for example, blows to the head from objects; penetrating injuries from missiles, bullets, and shrapnel; falls; skull fractures with resulting penetration by bone pieces; and sudden acceleration or deceleration injuries.
Traumatic brain injury represents a growing medical problem in the United States and elsewhere. It is an extremely costly illness, not only due to the expenses arising from the acute care required, but also due to the costs associated with rehabilitation and any resulting long-term disability. A therapy that would accelerate the recovery process and/or improve outcome would be highly beneficial to afflicted persons. As many as 40% of persons with severe head injury proceed to develop epilepsy, which further impedes functional recovery from traumatic brain injury. In addition, epilepsy itself further limits function in this population. A therapy that prevents the genesis of epilepsy would therefore significantly benefit traumatically brain injured persons.
Memory Disorders
A third form of neural plasticity relates to the treatment of chronic memory disorders. These disorders arise from, for example, Alzheimer""s Disease, encephalitis, cerebral palsy, Wernicke-Korsakoff (alcohol-related) syndrome, brain injury, post-temporal lobectomy, Binswanger disease, Parkinson""s disease, Pick""s disease, stroke, multi-stroke dementia, multiple sclerosis, post arrest hypoxic injury, near drowning, etc.
As demonstrated in the non-limiting Examples disclosed infra, vagus nerve stimulation employed with the appropriate parameters can improve memory and learning in human and animal subjects. When delivered shortly after a learning experience, vagus nerve stimulation results in the initiation of nerve impulses that travel to those brain structures where the nerve terminates, predominantly the nucleus of the solitary tract. The resultant release of neurotransmitters and activation of cells in the vagus nerve target structures results in the activation of other brain areas including those such as the amygdala and hippocampus that are known to be involved in memory storage and the modulation of memory. The result is facilitated memory storage (consolidation) and improved retention performance when memory is measured at some later time. Vagus nerve stimulation can also be employed in the treatment of human and animal subjects suffering from various forms of brain damage or from traumatic head injury.
It is well known that central nervous system neurons do not regenerate following loss due to disease or injury. Therefore, in order for there to be recovery of function, healthy areas of the brain must xe2x80x9clearnxe2x80x9d to take over the functions of the damaged area.
As discussed above, both phenomena are manifestations of brain neural plasticity.
Briefly, therefore, the present invention provides a number of methods of influencing various aspects of brain neural plasticity. In one embodiment, the present invention is directed to a method of modulating brain neural plasticity in a human or animal subject. The method comprises applying a stimulating electrical signal to the vagus nerve of a human or animal subject. The stimulating electrical signal being effective to cause a physiological, structural, or neuronal connective alteration in the brain. Neural function in the brain is changed as a consequence of the neuronal connective alteration; thereby changing behavior, or the capacity for behavior, in the human or animal subject.
In another embodiment, the present invention is directed to a method of improving learning or memory in a human or animal subject. The method comprises
(a) applying a stimulating electrical signal to the vagus nerve of a human or animal subject, the stimulating electrical signal being effective to enhance memory storage or consolidation processes in the human or animal subject; and (b) improving memory storage or improving the retention of learning experiences, in the human or animal subject.
In another embodiment, the present invention is directed to a method of treating a human or animal subject suffering from a symptom caused by traumatic brain injury or characteristic of traumatic brain injury. The method comprises selecting a human or animal subject suffering from a symptom caused by traumatic brain injury or characteristic of traumatic brain injury; and applying a stimulating electrical signal to the vagus nerve of the human or animal subject, the stimulating electrical signal being effective to alleviate the symptom caused by or characteristic of traumatic brain injury. The method further comprises monitoring the human or animal subject via a member selected from the group consisting of clinical outcome, a clinical test, a laboratory test, and combinations thereof, to determine if the symptom has been alleviated, or if further stimulation of the vagus nerve is required. If required, the vagus nerve is further stimulated and the subject is further monitored as in the preceding steps, until the symptom has been alleviated.
In another embodiment, the present invention is directed to a method of preventing the development of epilepsy in a human or animal subject. The method comprises selecting a human or animal subject predisposed to, or rendered susceptible to, developing epilepsy; and applying a stimulating electrical signal being effective to prevent epilepsy to the vagus nerve of the human or animal subject. The method further comprises monitoring the subject to determine if further stimulation of the vagus nerve is required to prevent epilepsy in the subject; and if required, further stimulating the vagus nerve and monitoring the subject as in the preceding steps, to prevent development of epilepsy in the subject.
In another embodiment, the present invention is directed to a method of treating a human or animal subject suffering from a symptom selected from the group consisting of memory impairment, a learning disorder, impairment of cognitive processing speed, impairment of acquisition of perceptual skills, impairment of acquisition of motor skills, and impairment of perceptual processing. The method comprises selecting a human or animal subject suffering from a symptom selected from the group consisting of memory impairment, a learning disorder, impairment of cognitive processing speed, impairment of acquisition of perceptual skills, impairment of acquisition of motor skills, and impairment of perceptual processing; and applying a stimulating electrical signal to the vagus nerve of the human or animal subject. The electrical signal is characterized as being effective to alleviate the symptom in the human or animal subject. The method further comprises monitoring the human or animal subject via a method selected from the group consisting of a clinical test, a laboratory test, determination of clinical outcome, and combinations thereof, to determine if the symptom has been alleviated, or if further stimulation of the vagus nerve is required to alleviate the symptom; and if required, further stimulating the vagus nerve and monitoring the human or animal subject as in the preceding steps, until the symptom has been alleviated.
In another embodiment, the present invention is directed to a method of treating a human or animal subject suffering from persistent impairment of consciousness. The method comprises selecting a human or animal subject suffering from persistent impairment of consciousness; and applying a stimulating electrical signal to the vagus nerve of the human or animal subject. The stimulating electrical signal is characterized as being effective to alleviate the persistent impairment of consciousness in the human or animal subject. The method further comprises monitoring the human or animal subject via determination of clinical outcome to determine if the persistent impairment of consciousness has been alleviated, or if further stimulation of the vagus nerve is required to alleviate the persistent impairment of consciousness; and if required, further stimulating the vagus nerve and monitoring the human or animal subject as in the preceding steps, until the persistent impairment of consciousness has been alleviated.
Further scope of the applicability of the present invention will become apparent from the detailed description and drawings provided below. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the present invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.